Project Summary: This supplemental grant application is a translational drug discovery proposal in response to NOT-AG-18-039 for NIH Funding Opportunities - Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease. Our approach covers specific areas of interest including medicinal and computational chemistry, structural biology and pharmacological validation of novel therapeutics to treat AD and ADRD. Our ultimate goal is to develop novel, selective, CNS penetrant small molecule DYRK1A inhibitor therapeutics to treat AD/ADRD with data generated to apply for future funding opportunities. DYRK1A inhibitors in our current research program are directed for peripheral use to treat diabetes. We request supplemental funding to characterize our new lead scaffolds for CNS penetrance and activity in AD/ADRD cell based and in vivo assays of AD mouse models. The data generated will be useful to optimize our inhibitors neurological diseases such as ADRD and then apply for future funding for further AD drug development. Our premise is that novel leads, developed for the specific use in the CNS will provide further validation of this target for ADRD. Our strategy of structure based drug design and medicinal chemistry kinase optimization, coupled with powerful in vitro and in vivo assays will lead to improved CNS penetrant DYRK1A inhibitors. To that end, we have identified novel drug-like leads that target DYRK1A. These results provide the basis for a drug discovery effort that includes a molecular target, in vitro/in vivo ADRD biology, and viable starting points for medicinal chemistry optimization. Based on these complementary capabilities and important objectives and implications for DYRK1A in AD therapeutics, we propose three specific aims: Specific Aim 1. Develop two novel, structurally distinct DYRK1A inhibitors with kinase/off-target selectivity, oral bioavailability and brain penetration for AD therapy using structure-based drug design. Specific Aim 2. Evaluate novel compounds for DYRK1A inhibition, in vitro ADME-PK, optimized off- target selectivity, effects on cellular tau phosphorylation using biochemical and cell-based assays. Specific Aim 3. Evaluate optimized DYRK1A inhibitors for in vivo ADME PK, brain penetration, effects on tau and other AD associated proteins using in vivo microdialysis and efficacy in AD mouse models.